Martin Holder

(Val-)Ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation

Epstein‐Barr virus (EBV) primary infection constitutes a serious risk for pediatric transplant recipients, particularly as regards the development of EBV‐related post‐transplant lymphoproliferative disease (PTLD). Currently, there is no established prophylactic regimen. We investigated the association between chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) and the incidence of EBV viremia in EBV‐naïve pediatric renal transplant recipients (R−) who had received a graft from an EBV‐positive donor (D+) and are therefore at high risk of EBV primary infection. In a prospective, multicenter trial (n = 114), we compared a cohort on chemoprophylaxis (n = 20) with a similar control cohort without chemoprophylaxis (n = 8). Over the 1‐year study period, antiviral prophylaxis with VGCV/GCV was associated with a significantly decreased incidence of EBV primary infection: 9/20 patients (45%) in the prophylaxis group experienced an EBV primary infection compared to 8/8 controls (100%) (P < 0.0001). Chemoprophylaxis was associated with a significantly lower EBV viral load (P < 0.001). Type or intensity of immunosuppressive therapy did not influence the occurrence of EBV primary infection or the level/persistence of EBV viral load. Chemoprophylaxis with VGCV/GCV is associated with a reduced incidence of EBV viremia in high‐risk pediatric kidney allograft recipients in the first year post‐transplant.

Epidemiology and Morbidity of Epstein-Barr Virus Infection in Pediatric Renal Transplant Recipients: A Multicenter, Prospective Study

BACKGROUND The epidemiology and morbidity of Epstein-Barr virus (EBV) infection in pediatric renal transplant recipients have been characterized insufficiently. METHODS In a prospective, multicenter study among 106 pediatric kidney allograft recipients aged 11.4 ± 5.9 years, we investigated the epidemiology of EBV infection and the relationship between EBV load, EBV serology, and EBV-related morbidity (posttransplant lymphoproliferative disease [PTLD] or symptomatic EBV infection, defined as flu-like symptoms or infectious mononucleosis). RESULTS EBV primary infection occurred in 27 of 43 (63%) seronegative patients and reactivation/reinfection in 28 of 63 (44%) seropositive patients. There was no association between the degree or duration of EBV load and EBV-related morbidity: The vast majority (17 of 18 [94%]) of patients with a high, persistent EBV load remained PTLD-free throughout a follow-up of 5.0 ± 1.3 years, while 2 of 3 (66%) patients with EBV-related PTLD exhibited only a low EBV load beforehand. Eight of 18 (44%) patients with a high, persistent EBV load remained asymptomatic during a follow-up of 5.3 ± 2.9 years. Multivariate analysis identified the EBV high-risk (D(+)/R(-)) serostatus (odds ratio [OR], 7.07; P < .05), the presence of human leukocyte antigen (HLA)-DR7 (OR, 5.65; P < .05), and the intensity of the immunosuppressive therapy (OR, 1.53; P < .01) as independent risk factors for the development of a symptomatic EBV infection. CONCLUSIONS Presence of EBV high-risk seroconstellation, HLA-DR7, and intensity of immunosuppressive therapy are significant risk factors for a symptomatic EBV infection, whereas there is no close association between the degree or duration of EBV load and EBV-related morbidity. Clinical Trials Registration. NCT00963248.

Continuous glucose monitoring in children, adolescents, and adults with type 1 diabetes mellitus: analysis from the prospective DPV diabetes documentation and quality management system from Germany and Austria

Ludwig‐Seibold CU, Holder M, Rami B, Raile K, Heidtmann B, Holl RW; for the DPV Science Initiative, the German Working Group for insulin pump treatment in pediatric patients and the German BMBF Competence Network Diabetes. Continuous glucose monitoring in children, adolescents, and adults with type 1 diabetes mellitus: analysis from the prospective DPV diabetes documentation and quality management system from Germany and Austria.

Pharmacokinetics and Immunodynamics of Basiliximab in Pediatric Renal Transplant Recipients on Mycophenolate Mofetil Comedication

Background. The aim of this substudy within a prospective, multicenter, placebo-controlled trial was to assess the pharmacokinetics and immunodynamics of basiliximab in pediatric renal transplant recipients on comedication with mycophenolate mofetil (MMF). Methods. Eighty-two patients aged 3 to 18 years, receiving cyclosporine microemulsion, MMF, corticosteroids, and basiliximab or placebo were investigated. Basiliximab serum concentrations were determined by ELISA, CD25+, and CD122+ T lymphocytes by flow cytometry. Results. Basiliximab clearance adjusted to body surface area was significantly (P<0.05) greater in children versus adults, but the relatively higher basiliximab dose given to children yielded similar exposure compared with adolescents. A cross-study comparison revealed that MMF reduced basiliximab clearance and prolonged CD25 saturation duration from approximately 5 weeks in the absence of MMF to 10 weeks in the presence of MMF. Basiliximab led to a marked reduction of CD25+ T-cell fraction during the first 8 to 10 weeks posttransplant, but did not specifically affect CD122+ T cells. The majority of biopsy-proven acute rejection episodes (BPAR) were observed after interleukin (IL) 2-R desaturation, whereas about a quarter of BPARs occurred despite adequate IL2-R blockade. Conclusions. The currently recommended basiliximab dose for pediatric patients, when used with cyclosporine microemulsion and corticosteroids, yielded adequate drug exposure in children and adolescents also under MMF comedication. The observation that about a quarter of BPARs occurred despite adequate IL2-R blockade suggests that another T-cell activation pathway independent of the IL-2/IL-2R pathway is operative, for example, the IL-15 signaling pathway.

Natural course of untreated microalbuminuria in children and adolescents with type 1 diabetes and the importance of diabetes duration and immigrant status: longitudinal analysis from the prospective nationwide German and Austrian diabetes survey DPV

OBJECTIVE To identify risk factors for the development and progression of untreated persistent microalbuminuria in children and adolescents with type 1 diabetes. DESIGN AND METHODS A total number of 683 children and adolescents with type 1 diabetes recruited from the prospective nationwide German and Austrian diabetes survey (DPV) were included in the analysis. Inclusion criteria were onset of type 1 diabetes under the age of 11 years, diabetes duration of more than 1 year and continuous follow-up over 5 years with at least two documented urine analyses per year. Subjects treated with angiotensin-converting enzyme inhibitors were excluded. Risk factors such as sex, body mass index SDS, diabetes duration, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, systolic and diastolic blood pressure, and immigrant status were analysed by logistic regression. RESULTS At baseline (age 10.5 ± 0.1 years, diabetes duration 4.6 ± 2.4 years and HbA1c 7.4 ± 1.1%), 75.6% of children had normoalbuminuria, 15.7% had intermittent microalbuminuria, 8.6% had persistent microalbuminuria and 0.1% had macroalbuminuria. After a follow-up of 5 years, 59.4% of adolescents continued to have normoalbuminuria, 18.4% had progression, 15.2% had regression of microalbuminuria, and in 6.9% of the subjects, microalbuminuria remained unchanged. We found significant associations between persistent microalbuminuria at baseline and during each year of follow-up (P < 0.0001). Logistic regression analysis identified diabetes duration and immigrant status as significant factors for microalbuminuria (P = 0.009 and P = 0.009). CONCLUSIONS The survey in a real-world setting shows that diabetes duration and immigrant status are risk factors for the development and progression of untreated microalbuminuria in children and adolescents with type 1 diabetes.

Influence of Long-Term Glycemic Control on the Development of Cardiac Autonomic Neuropathy in Pediatric Patients with Type I Diabetes

Few data are available about autonomic dysfunction in children and adolescents with diabetes. Especially in the early stages, computer-based heart-rate analysis may be sensitive enough to detect cardiac autonomic neuropathy where standard methods fail (1,2). We used the newly developed ProSciCard-System (Medi-Syst, Linden, Germany) (3) to measure subclinical signs of cardiac autonomic neuropathy in pediatric patients with type I diabetes and to determine the influence of long-term giycemic control, age, and duration of diabetes on the incidence of autonomic dysfunction. In 204 pediatric patients (106 girls and 98 boys; mean age, 16.5 ± 4.3 years; mean duration of diabetes, 7.9 ± 5.3 years) and in 28 healthy normal children (14 girls and 14 boys; age range, 10-19 years), the coefficient of variation in supine and standing position during deep breathing and the Valsalva ratio were determined, and the Ewing test (max./min., 30:15 ratio) was performed. The data were recorded prospectively by computer documentation (4). The results of normal and abnormal test responses are summarized in Table 1. The median of all HbAlc values during the entire duration of diabetes increased significantly in patients with two or more pathological test results (P < 0.001 by KruskalMetabolic Control

Cardiovascular risk in pediatric type 1 diabetes: sex-specific intima-media thickening verified by automatic contour identification and analyzing systems.

Krebs A, Schmidt‐Trucksäss A, Doerfer J, Grulich‐Henn J, Holder M, Hecker W, Krebs K, Barth M, Schwab KO. Cardiovascular risk in pediatric type 1 diabetes: sex‐specific intima‐media thickening verified by automatic contour identification and analyzing systems.

Increased renal echogenicity in a preterm neonate: Question

A 34-year-old otherwise healthy Caucasian female with severe hypertension became pregnant. Because of unknown circumstances her pregnancy was not diagnosed until 26 weeks of gestation. Sonographic examination at that time showed no evidence of oligohydramnion or malformation of the fetus. At 31 weeks of gestation, premature rupture of the membranes occurred and a female newborn was delivered by c-section with a birth weight of 1680 g, a length of 40 cm and a head circumference of 28 cm (all 50th percentile). Histological examination of the placenta revealed signs of chorioamnionitis. The newborn suffered from perinatal asphyxia and primary support included intubation, fluid challenge, and correction of acidosis with bicarbonate. Apgar scores after 5 and 10 min were 4 and 7, respectively. After one dose of surfactant the clinical situation significantly improved and the girl could be extubated on the third day of life. An infection was presumed and antibiotic therapy was initiated. On day 5 a patent ductus arteriosus was diagnosed, but spontaneous closure occurred. There was no decrease in urine output, and blood-pressure readings were within normal limits. Physical examination of the newborn revealed subtle contractions of the extremities and distended cranial sutures, but no further malformations. She seemed hypotonic but there were no clinical or encephalographic signs of seizure activity in the first week of life. Because of pathological abnormalities in a repeat EEG, however, phenobarbital was started and continued for a total of 4 weeks. On day 12, a sonographic examination of the abdomen revealed two kidneys with markedly increased echogenicity and normal size without any cyst formation (Fig. 1). Doppler sonography revealed reduced diastolic blood flow in the renal arteries and an elevated resistance index of 0.83. Because of the echogenic kidneys a diagnostic work-up was started. The girl was healthy, without edema, and had normal urine output and normal blood pressure readings (74– 88 mmHg systolic and 43–62 mmHg diastolic). Laboratory values at initial presentation and during follow-up are shown in the table. Urinalysis revealed up to 5 white blood cells and 3 red blood cells per milliliter, but no significant proteinuria. Urinary calcium and oxalate excretion ratios were in the normal range (Table 1). The answer to this question can be found at http://dx.doi.org/ 10.1007/s00467-005-1938-1

Decreased levels of homoarginine and asymmetric dimethylarginine in children with type 1 diabetes: associations with cardiovascular risk factors but no effect by atorvastin

Abstract Objectives: To investigate homoarginine and asymmetric dimethylarginine (ADMA) in controls compared to children with type 1 diabetes (T1D) and if homoarginine and ADMA are affected by atorvastatin. Methods: Homoarginine and ADMA levels of 28 T1D patients were compared to levels of 41 controls. In T1D patients, homoarginine and ADMA were determined at baseline, 1 year, and 2 years at daily 10 mg atorvastatin or placebo within a double-blind study. Results: At baseline, both homoarginine and ADMA were lower (p<0.001) in T1D patients compared to controls. In T1D patients, homoarginine and ADMA were not influenced by atorvastatin. Inverse correlations between homoarginine and HbA1c (p<0.001) and between ADMA and systolic blood pressure (p=0.005) and pulse pressure (p=0.003) were shown. Conclusions: Homoarginine and ADMA levels are decreased and associated with cardiovascular risk factors in children with T1D without being affected by atorvastatin.

Lipoprotein-associated phospholipase A2 activity and low-density lipoprotein subfractions after a 2-year treatment with atorvastatin in adolescents with type 1 diabetes.

Abstract Background: The objective of the study was to assess the effect of atorvastatin on inflammation markers and low-density lipoprotein (LDL) subfractions. Methods: In a prospective, randomized, double-blind pilot study involving 28 adolescents with type 1 diabetes (T1D), lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, high-sensitivity C-reactive protein (hsCRP), and subfractions of LDL were measured at baseline, after 1 year and 2 years of treatment with atorvastatin (10 mg/day) vs. placebo. Results: For the atorvastatin group, we found posttreatment reductions of Lp-PLA2 activity (p<0.001), LDL cholesterol (p=0.001), non-small dense LDL cholesterol (p<0.001), total cholesterol (p<0.001), and apolipoprotein B (apo B) (p<0.001), whereas small dense LDL cholesterol and hsCRP did not change significantly. Conclusions: In adolescents with T1D, long-term treatment with atorvastatin is safe and may reduce cardiovascular risk by significant decreases of Lp-PLA2 activity and LDL cholesterol.